70 KD HSPS--MODULATORS OF DEVELOPMENTAL TOXICITY

描述：尽管各种物理和化学物质破坏了 在动物和人类的发育过程中，人们对影响 确定特定的动物或人类是否会对 潜在的发育毒性暴露。最近的研究发现 一个基因家族及其各自的蛋白质，被称为70千道尔顿热 休克蛋白(HSP 70)家族，在保护细胞和 暴露在高温和化学物质下的器官毒性效应 侮辱。此外，来自作者实验室和其他机构的研究 实验室已经证实这些热休克蛋白是 哺乳动物胚胎的发育毒性。为了更准确地确定 特异性热休克蛋白在调节发育中的作用 毒性方面，提出了三个具体目标。在具体目标1中，是 建议使用过度表达特定热休克的转基因小鼠 用于测试可诱导Hsp70过表达将 降低小鼠移植后早期胚胎对 选定的发育毒物的致畸作用。在具体目标2中， 建议使用HSP 70-1和HSP 70-3转基因小鼠 基因已通过同源重组失活，以测试 假设热休克蛋白70-1/3缺失会增加早期 小鼠移植后胚胎对转基因效果的影响 发育毒物。在具体目标3中，建议使用这些 功能获得和功能丧失转基因研究 热休克蛋白70-1/3通过相互作用发挥调节活性的假说 通过细胞周期机制，从而防止不适当的细胞死亡。 在这项拟议的工作中，发育毒物将是高热和 环磷酰胺。

DESCRIPTION: Although a variety of physical and chemical agents disrupt development in animals and humans, little is known about factors that determine whether a particular animal or human will be sensitive to a potentially developmentally toxic exposure. Recent research has identified a family of genes and their respective proteins, known as 70 kilodalton heat shock protein (Hsp 70) family, that plays a role in protecting cells and organs from the toxic effects of exposure to hyperthermia and chemical insult. In addition, research from the author's laboratory and other laboratories has implicated these heat shock proteins as modulators of developmental toxicity in mammalian embryos. To determine more precisely the role of specific heat shock proteins in modulating developmental toxicity, three specific aims are proposed. In specific aim 1, it is proposed to use transgenic mice that overexpress specific heat shock proteins to test the hypothesis that overexpression of inducible Hsp70 will decrease the sensitivity of early postimplantation mouse embryos to the teratogenic effects of selected developmental toxicants. In specific aim 2, it is proposed to use transgenic mice in which the Hsp 70-1 and Hsp 70-3 genes have been inactivated by homologous recombination to test the hypothesis that loss of Hsp 70-1/3 will increase the sensitivity of early postimplantation mouse embryos to the transgenic effects of selected developmental toxicants. In specific aim 3, it is proposed to use these gain-of-function and loss-of-function transgenics to investigate the hypothesis that Hsp 70-1/3 exerts its modulating activity by interacting with the cell cycle machinery, thereby preventing inappropriate cell death. In the work proposed the developmental toxicants will be hyperthermia and cyclophosphamide.